Overproduction of NO by an inducible
NO synthase (iNOS) plays a major role in the pathophysiology of
septic shock, and selective inhibition of iNOS in this setting could be of great therapeutic value. In the present study, we evaluated the effects of L-
canavanine, a selective iNOS inhibitor, in an animal model of
septic shock, with a particular focus on tissue oxidative metabolism and organ functions. Anesthetized rats challenged intravenously with lipopolysacharide (LPS) were treated after 1 h by a continuous infusion of either L-
canavanine (20 mg/kg/h; n = 11) or an equivalent volume of saline (2 ml/kg/h; n = 17) given for 4 h. A third group (
sham rats; n = 9) did not receive LPS and was treated with a continuous infusion of saline (2 ml/kg/h). At the end of experiments, biopsies were taken from the liver, the kidney, and the small intestine for the measurement of tissue
ATP. LPS induced a progressive fall in blood pressure, accompanied by
biologic signs of liver and
kidney failure, concomitant with a marked decrease in tissue
ATP stores. L-
canavanine largely prevented
hypotension and significantly increased tissue
ATP while reducing the signs of organ dysfunction. These effects were associated with a significant improvement in survival during the 5 h of study. We conclude that L-
canavanine not only reduces
hypotension in
endotoxin shock but also largely prevents the detrimental consequences of LPS on tissue oxidative metabolism and major organ functions, allowing a decrease in
endotoxin lethality.